Abstracts

Status epilepticus (SE) is a medical and neurological emergency. The annual incidence in the US is exceeding 100.000 cases of which approximately 20% result in death. Progressive neuronal damage occurs if convulsive SE persists for more than 30 minutes. During SE the extracellular levels of glutamate increase to neurotoxic levels, which is believed to play an important role for the brain damage.
NS1209 is a potent and selective, competitive AMPA antagonist. A neuroprotective effect has been demonstrated in both global and focal models of cerebral ischemia where treatment started up to 3 hours post occlusion. NS1209 has very pronounced anticonvulsive effect in a number of seizure models, including rodent models of sound-induced and electroshock-induced seizures. NS1209 has also shown a complete block of seizures in two models of SE. Compared to currently available treatment of SE, NS1209 produces a seizure blocking effect, prevents epileptogenesis and has a potential neuroprotective effect.In phase 1 studies NS1209 has been well tolerated by healthy volunteers at plasma concentration levels of two to four times higher than the preclinical levels demonstrating neuroprotection.
As part of the clinical development 12 patients in two cohorts received a single bolus injection followed by a 2 or 4-hour infusion of NS1209. The purpose of the study was to investigate the extent to which NS1209 passes the human Blood Brain Barrier. In cohort 1 the patients received a 2-hour infusion, and the concentration of NS1209 was determined in the cerebrospinal fluid (CSF) and plasma at 3 and 9, or at 6 and 24 hours after start of dosing. In cohort 2 the infusion time was 4 hours, and CSF and plasma levels were determined 6 and 12 hours after treatment start. For both cohorts the bolus dose was 14mg of NS1209, and the infusion rate was 77 mg/hour.
The compound was well tolerated in all patients. The T[sub][frac12][/sub] was approximately 1 hour, and the maximal measured concentration in the CSF was obtained at the 6 hour time point in cohort 1. Based on the data C[sub]max[/sub] was anticipated to approximately 4 hours NS1209 was detected in the CSF of all the patients. Also was the compound still present in the CSF after 24 hours, although at very low concentration. The results from cohort 2 were not finally analysed at the submission deadline. These data will be presented.
The high risk of mortality and neuronal damage associated with SE using existing treatment paradigms highlight the need for new seizure stopping as well as neuroprotective strategies. The AMPA-antagonist NS1209 has shown neuroprotective effect in several preclinical ischemia models. Moreover has it shown very strong dose dependent anticonvulsant effect in various animal seizure models, inclusive two models of SE. Only very few and mild side effects have been reported in phase 1 studies. This study has showed, that NS1029 passes the human BBB. Further studies to see whether or not NS1209 has anticonvulsant effect in humans are needed.